Hertz Daniel L, Snavely Anna C, McLeod Howard L, Walko Christine M, Ibrahim Joseph G, Anderson Steven, Weck Karen E, Magrinat Gustav, Olajide Oludamilola, Moore Susan, Raab Rachel, Carrizosa Daniel R, Corso Steven, Schwartz Garry, Peppercorn Jeffrey M, Evans James P, Jones David R, Desta Zeruesenay, Flockhart David A, Carey Lisa A, Irvin William J
University of Michigan, Ann Arbor, MI48109-1065, USA.
RTI International, Research Triangle Park, NC, 27709-2194, USA.
Br J Clin Pharmacol. 2015 Nov;80(5):1122-30. doi: 10.1111/bcp.12665. Epub 2015 Aug 2.
A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles.
Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen : N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively.
Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014).
The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.
应用前瞻性纳入的患者队列评估通过对双倍体型或等位基因重新分类，能否改善从基因型数据预测CYP2D6表型活性。
对355例接受20mg他莫昔芬治疗的患者进行CYP2D6基因分型，并测定他莫昔芬代谢物浓度。作为CYP2D6活性替代指标的4-羟基他莫昔芬：N-去甲基他莫昔芬代谢比，在通常合并为中间代谢型（IM）表型的四种双倍体型（EM/IM、EM/PM、IM/IM、IM/PM）之间进行比较。估计每种等位基因类型（超快速代谢型、正常代谢型、中间代谢型和慢代谢型）以及每种正常代谢型和中间代谢型等位基因的相对代谢活性，以便与通常分别指定的活性评分2、1、0.5和0进行比较。
四种IM双倍体型彼此之间以及与EM和PM表型组均具有不同的CYP2D6活性（各P<0.05）。将正常代谢型等位基因的活性设定为1.0时，超快速代谢型、中间代谢型和慢代谢型等位基因的相对活性分别为0.85、0.67和0.52。正常代谢型等位基因的活性具有统计学差异（P<0.0001），CYP2D6*2等位基因（标准化活性=0.63）的活性更接近中间代谢型而非正常代谢型等位基因。中间代谢型等位基因的活性也具有统计学差异（P=0.014）。
目前将CYP2D6基因型转化为表型的系统校准不佳，尤其是在中间代谢型双倍体型和*2等位基因方面。需要进行更多研究以改善从基因数据预测CYP2D6活性，从而实现CYP2D6依赖药物的个体化给药。
